Human mesothelioma induced by asbestos is a step-by-step accumulation of genetic modifications including chromosomal amplifications and deletions. Three major histologic subtypes have been already identified: epithelioid, sarcomatoid and biphasic. To compare these subtypes, cell lines exhibiting a pure epithelioid, a pure sarcomatoid and mixed phenotypes were studied using array-based comparative genomic hybridization. For the epithelioid lines these studies revealed homogeneous deletions and duplications for several chromosomes ranging from 1 to 97.5 Mb. The abnormalities affected complete or partial chromosomes, and chromosome losses were more common than gains. In contrast, no abnormality was detected using this technique in the sarcomatoid and biphasic cell lines. However, more detailed analysis of the 9p21 region and its gene products by Fluorescence in situ hybridization (FISH), quantitative polymerase chain reaction (PCR) and fluorescence activated cell sorting (FACS) revealed the loss of p14ARF expression, a product of cyclin-dependent kinase inhibitor 2A (CDKN2A) gene, in the sarcomatoid cell lines, while expression of p16INK4a, an alternative splicing isoform of the same gene, was retained. In the epithelioid cell lines the opposite situation was present with expression of p14ARF, but loss of p16INK4a. These studies confirm the importance of the tumour suppressor genes encoded at the 9p21 locus in the pathogenesis of mesothelioma. The present results may help in the development of prognostic factors and in better understanding the basic biological processes.
View Full Article